Background: Symptom clusters are the co-occurrence of two or more symptoms that are related. Assessing and treating symptom clusters in chronic illness may have a more favorable impact on health outcomes than targeting single symptoms. The symptom cluster dyspnea, fatigue and sleep disturbance is common and negatively affects health-related quality of life in people with pulmonary arterial hypertension (PAH). Determining underlying biological mechanisms is essential to develop and test biobehavioral interventions to target these mechanisms and alleviate symptoms. The pathobiology involved in PAH includes activation of the sympathetic nervous system (SNS) and inflammatory pathways which may prove to impact the symptom cluster in PAH. Inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF- alpha) have been associated with symptoms (dyspnea, fatigue and sleep disturbance) in other disorders. Preliminary evidence has shown an association between fatigue and IL-6 in PAH. Research: The proposed project in this K23 award is the step toward independence in a program of research in symptom management in chronic illness. In the proposed project we will determine if activation of the SNS [measured by plasma norepinephrine enzyme-linked immunosorbent assay (ELISA)] and inflammatory biomarker levels (measured by IL-6 and TNF-alpha ELISAs) are associated with symptom cluster severity [dyspnea measured by the US Cambridge Pulmonary Hypertension Outcome Review (US CAMPHOR), fatigue measured by the Multidimensional Fatigue Inventory (MFI), sleep disturbance measured by the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), actigraphy and sleep diary]. We will enroll 60 women with PAH who will complete the US CAMPHOR, MFI, PSQI, ESS and the PAH Symptom Severity Scale. Subjects will also complete 7-days of actigraphy along with a sleep diary. We will collect plasma norepinephrine, IL-6 and TNF-alpha levels. Our overall hypothesis is increased levels of plasma norepinephrine, IL-6 and TNF-alpha levels will be associated with symptom cluster severity in women with PAH. This study will form the basis for the candidate to develop targeted interventions to alleviate symptom clusters. This study has implications not only for PAH but other chronic, symptom-producing illnesses. Training: This component of the K23 is comprised of didactic and mentored experiences to enable the candidate to develop the proposed program of research as an independent scientist in patient-oriented research. The training plan builds on the candidate's prior experiences and provides the necessary training in inflammatory biomarkers, sleep measures, clinical trial design and advanced statistical methods. Training activities include course work, attendance and presentations at conferences and workshops along with one-on- one mentoring.